Novel stable crystal of thiazolidinedione derivative and process for producing the same

ABSTRACT

A homogeneous crystal having excellent stability which is suitable for the industrial-scale production of 5-[(2,4-dioxothiazolidin-5-yl)methyl]-2-methoxy-N-[[4-(trifluoromethyl)phenyl]methyl]benzamide (KRP-297). The novel crystal of KRP-297 is produced through recrystallization from an alcohol solvent. It is characterized by having diffraction angles (2θ) at at least 9.7°, 15.0°, and 22.5° in X-ray powder diffractometry.

TECHNICAL FIELD

[0001] The invention relates to a stable crystal form of5-[(2,4-dioxothiazolidin-5-yl)methyl]-2-methoxy-N-[[4-(trifluoromethyl)phenyl]methyl]benzamide(KRP-297) represented by a formula (1)

[0002] and a process for preparing it.

BACKGROUND TECHNIQUE

[0003] KRP-297 has very excellent glucose-lowering activity and is auseful compound as an hypoglycemic agent and an insulin sensitizer (M.Nomura et al, Bioorg. Med. Chem. Lett., 9 (1999) 533-538). At thebeginning, it was prepared through a process disclosed in Japanese KokaiHei 9-48771.

[0004] [subject to be Solved by the Invention]

[0005] The objective is to find out crystals homogeneous and excellentin stability and to establish a process for preparing them, in order toprepare KRP-297 on an industrial scale.

DISCLOSURE OF THE INVENTION

[0006] With the study and development of the preparative process ofKRP-297, the inventors have found that novel crystals different fromthose having been obtained through conventional process (Japanese KokaiHei 9-48771) can be obtained, leading to the completion of theinvention. Namely, it has been confirmed that, by additionallyrecrystallization of the crystals (old form crystals) of KRP-297obtained through conventional processes (for example, Japanese Kokai Hei9-48771 etc.) from a suitable solvent, they are converted to morehomogeneous and more stable novel crystals than conventional ones.

[0007] The novel crystals of KRP-297 are characterized by exhibiting thediffraction angles (2θ) at at least 9.7°, 15.0° and 22.5° in the X-raypowder diffraction.

[0008] The novel crystals of KRP-297 of the present invention canusually be obtained in good reproducibility by recrystallization of thecrude crystals obtained after completion of reaction from a suitablesolvent.

[0009] As the solvents to be used for recrystallization, lower alcoholssuch as ethanol, water-containing lower alcohols, common organicsolvents, mixed solvents if need be, and the like can be mentioned.Preferable solvent is ethanol or isopropyl alcohol.

[0010] The novel crystals of the invention have no hygroscopicity andmake it possible to supply stably in terms of preparation, which is veryadvantageous for the industrial production of KRP-297.

BRIEF DESCRIPTION OF THE DRAWING

[0011]FIG. 1 The X-ray powder diffraction diagram of the inventive novelcrystals.

[0012]FIG. 2 The X-ray powder diffraction diagram of the crystalsthrough conventional process.

[0013]FIG. 3 The thermal analysis diagram of the inventive novelcrystals.

[0014]FIG. 4 The thermal analysis diagram of the crystals throughconventional process.

THE BEST MODE FOR WORKING THE INVENTION EXAMPLE

[0015] In following, examples will be shown to illustrate the inventionin more detail, but the invention does not undergo any restriction bythese examples.

Example 1

[0016] To 49 mL of dichloromethane were added 6.30 g of triethylamineand 7.00 g of 5-[(2,4-dioxothiazolidin-5-yl) methyl]-2-methoxybenzoicacid. After 2.71 g of ethyl chlorocarbonate were added, the mixture wasstirred for 10 minutes. Further, 4.59 g of 4-trifluoromethylbenzylaminewere added and the mixture was stirred for 1 hour. After washed thereaction mixture with water, solvent was distilled off and to theresidue were added 109 mL of water and 33 mL of ethanol, to whichsolution 2 mol/L hydrochloric acid was added dropwise to adjust to pH2.0. The precipitated crystals were collected by filtration and washedwith water to obtain 10.25 g of crude crystals. By recrystallizing 10.25g of crude crystals twice from 90% ethanol, 6.49 g of5-[(2,4-dioxothiazolidin-5-yl)methyl]-2-methoxy-N-[[4-(trifluoromethyl)phenyl]methyl] benzamide(KRP-297) were obtained (yield 61.3%).

[0017] mp. 193-195° C.

Example 2

[0018] To 35 mL of isopropyl alcohol dissolving 5.00 g of5-[(2,4-dioxothiazolidin-5-yl)methyl]-2-methoxybenzoic acid and 4.50 gof triethylamine, 2.12 g of ethyl chlorocarbonate were added dropwise at−5 to 0° C. with stirring. After stirring the mixture for 10 minutes at−5 to 0° C., a solution dissolving 3.27 g of4-trifluoromethylbenzylamine into 15 mL of isopropyl alcohol was addeddropwise to the mixture at −5 to 0° C. After the addition, the mixturewas warmed and stirred for 1 hour at 25 to 35° C. Then, the temperaturewas raised to 60° C. and, after 4.83 mL of 24.5% aqueous solution ofsodium hydroxide were added thereto, the mixture was cooled to 3° C. andthe precipitated sodium salt was collected by filtration, which was thenwashed with 15 mL of isopropyl alcohol.

[0019] The sodium salt obtained was dissolved into a mixed solution of78 mL of water and 59 mL of isopropyl alcohol and the solution wasadjusted to pH 6.95 with 1 mol/L hydrochloric acid. After cooling it to6° C., the precipitated crystals were collected by filtration, whichwere then washed with 23 mL of water. These were dried at 40° C. withblowers to obtain 6.59 g (yield 84.6%) of crude crystals.

[0020] These crude crystals were recrystallized from 132 mL of 90%ethanol and then dried at 40° C. under reduced pressure to obtain 6.02 g(yield 77.3%) of KRP-297.

[0021] mp. 195-196° C.

Example 3

[0022] To 36.3L of isopropyl alcohol dissolving 5.20 kg of5-[(2,4-dioxothiazolidine-5-yl)methyl]-2-methoxybenzoic acid and 4.68 kgof triethylamine, 2.11 kg of ethyl chlorocarbonate were added dropwisewhile keeping it at −5 to 0° C., under stirring. After stirring it for10 minutes at −5 to 0° C., a solution dissolving 3.24 kg of4-trifluoromethylbenzylamine into 15.6L of isopropyl alcohol was addeddropwise thereto while keeping the same temperature. After thecompletion of dropwise addition, the mixture was warmed and stirred for1 hour at 25 to 35° C. Then, 20.8L of isopropyl alcohol were addedthereto, followed by adding 5.0L of 24.5% aqueous solution of sodiumhydroxide. The mixture was cooled to under 10° C., stirred for 1.5hours, and the precipitated sodium salt was collected by filtration,which was then washed with 15.6L of isopropyl alcohol. From the value ofdrying loss, 7.78 kg (91.4%) of the sodium salt of KRP-297 wereobtained.

[0023] The sodium salt obtained was dissolved into a mixed solution of77.8L of water and 72.9L of isopropyl alcohol, and 1 mol/L hydrochloricacid was added dropwise thereto at 0 to 10° C. to adjust to pH 2.0.

[0024] The solution was stirred for 1.5 hours at 0 to 10° C. and theprecipitated crystals were collected by filtration, which were thenwashed with 81.1L of water. From the value of drying loss, 6.12 kg(75.5%) of KRP-297 were obtained. These crude crystals were added to amixed solution of 28.6L of water and 122L of isopropyl alcohol andheated to over 70° C. to dissolve, which was then filtered while hot andwashed with a mixed solution of 2.4L of water and 9.8L of isopropylalcohol. The mixed solutions were combined, allowed to cool to roomtemperature, and stirred for 15 hours. The precipitated crystals werewashed with 18.4L of isopropyl alcohol, drained, and then dried at 40°C. under reduced pressure to obtain 5.32 kg (yield 65.6%) of KRP-297.

[0025] mp. 195-196° C.

Example 4

[0026] Into 119L of 90% ethanol were dissolved 5.97 kg of old formKRP-297 crystals (mp. 176.0-177.5° C.) obtained through the conventionalprocess (Example 39 of Japanese Kokai Hei 9-48771) under heat. Afterfiltered while hot, the residue was washed with 12L of 90% ethanol andthe filtrates were cooled to room temperature.

[0027] The precipitated crystals were collected by filtration and washedwith 18L of ethanol. These were dried at 40 to 60° C. to obtain 5.11 kg(85.6%) of novel crystals of KRP-297.

[0028] mp. 195° C.

Example 5 Measurement of X-Ray Powder Diffraction

[0029] The X-ray powder diffraction was measured by CuKα ray, using amodel X-ray diffractometer (Rigaku Co.). The diffraction angle (2θ) andthe relative intensity (cps) for the crystals of a compound in exampleare shown in FIG. 1. The X-ray powder diffraction pattern for thecrystals obtained through the conventional process is shown in FIG. 2.As a result, the crystals obtained in example of the invention exhibit acharacteristic diffraction pattern at at least 2θ=9.7°, 15.0° and 22.5°,which differs from that of conventional crystals.

Example 6 Thermal Analysis

[0030] Using the thermal analysis apparatus (Rigaku Denki; TAS-200), thethermal stability of the crystals were examined.

[0031] The thermal analysis chart for the novel crystal of KPR-297 wasshown in FIG. 3, while the thermal analysis chart for the crystalobtained by the conventional method was shown in FIG. 4.

[0032] In the novel crystal, endothermic phenomena were observed from194.8° C. and the endothermic peak was recognized at 186.3° C.

[0033] From this fact, it has become apparent that the novel crystal isone which is more thermally stable, compared with the conventionalcrystal.

APPLICABILITY ON INDUSTRIES

[0034] By additionally recrystallizing the crystals of KRP-297 obtainedthrough conventional process from an alcoholic suitable solvent,homogeneous and more stable novel crystals were obtained. Thehomogeneous and more stable novel crystals provided according to theinvention have no hygroscopicity and make it possible to supply stablyin terms of preparation, which is very advantageous in the industrialproduction of KRP-297.

1 novel crystals of5-[(2,4-dioxothiazolidin-5-yl)methyl]-2-methoxy-n-[[4-(trifluoromethyl)phenyl]methyl] benzamide, characterized by exhibiting the diffraction angles(2θ) at at least 9.7°, 15.0° and 22.5° in the x-ray powder diffraction:2 A process for preparing the novel crystals of claim 1, characterizedby recrystallization from a suitable solvent. 3 The process of claim 2for preparing the novel crystals, characterized by recrystallizationfrom lower alcohol or water-containing lower alcohol.